2,3-dihydro-2-oxo-1h-1,4-benzodiazepine-3-carboxylic acid esters and related compounds

ABSTRACT

The disclosure is directed to 2,3-dihydro-2-oxo-1H-1,4benzodiazepine-3-carboxylic acid esters; 2,3-dihydro-3-hydroxy-2oxo-1H-1,4-benzodiazepine-3-carboxylic acid esters and 3-alkoxy2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylic acid esters and to novel methods for their preparation. The compounds have therapeutic activity as central nervous system depressants and as intermediates in the production of 3-alkoxy-1,3-dihydro-2H-1,4benzodiazepin-2-ones, and 1,3-dihydro-3-hydroxy-2H-1,4benzodiazepin-2-ones.

United States Patent McCaully [451 July 18, 1972 s412,3-DIHYDRO-2-0XO-lH-l,4- 3,371,083 2/1968 Fryer et a1. ..260/239.3BENZOD]AZEPINE.3.CARBOXYLIC 3,371,084 2/1968 Fryer et al. ..260/239.338" ESTERSS AND RELATED FOREIGN PATENTS OR APPLICATIONS 650,637 12/1965Netherlands ..260/239.3 [72] Inventor: Ronald J. McCaully, Malvem,Chester,

Primary Examiner-l-lenry R. Jiles Assistant Examiner-Robert T. Bond [73]Asslgnee' g gz gr Produm Corporation Attorney-Andrew Kafko, Edmund H.O'Brien, Joseph Martin Weigman and Dwight J. Potter [22] Filed: March14, 1966 21 App]. No.2 533,854 [57] ABSTRACT The disclosure is directedto 2,3-dihydro-2-oxo-IH-1,4- benzodiazepine-3-carboxylic acid esters;2,3-dihydro-3- [52] U.S. Cl. ..260/239.3 hydroxy z oxo l lAbenzodiazepine 3 carboxylic acid 51 l t. Cl 141/00 esters and3-alkoxy-2,3-dihydro-2-oxo-lH-1,4- Id 3 239 3 Dbenzodia2epine-3-carboxylic acid esters and to novel methods I 1 e o mfor their preparation. The compounds have therapeutic activity ascentral nervous system depressants and as intermediates [56] Referencesin the production of 3-alkoxy-l,3-dihydro-2H-l,4- UNITED STATES PATENTSbenzodiazepin-Z-ones, and l,3-dihydro-3-hydroxy-2H-l,4-

benzodrazepm-Z-ones. 3,100,770 8/1963 Fryer et a]. ..260/239.3 3,270,0538/1966 Reeder et al ..260/239.3 13 Claims, No Drawings2,3-DlHYDRO-2-OXO-1H-l ,4-BENZODlAZEPlNE-3- CARBOXYLIC ACID ESTERS ANDRELATED COMPOUNDS C O O R 112 N wherein R and R are each selected fromthe group consisting of hydrogen, halogen, nitro, halo(lower)alkyl, andlower alkylsulfonyl; R is selected from the group consisting of thienyl,phenyl, halophenyl, lower alkoxyphenyl and halo(lower)alkylphenyl; R isselected from the group consisting of hydrogen, hydroxy and loweralkoxy; and R is lower alkyl. Specific examples of such compoundsinclude: 7-chloro-2,3- dihydro-Z-oxo-S-phenyl-l H- l,4-benzodiazepine-3-carboxylic acid, ethyl ester;7-chloro-2,3-dihydro-3-hydroxy-2-oxo-5-phenyl-lH-l,4-benzodiazepine-3-carboxylic acid, ethyl ester and7-chloro-2,3-dihydro-3-methoxy-2-oxo-5-phenyll H- l ,4-benzodiazepine-3-carboxylic acid, ethyl ester.

In accord with a process aspect of the present invention the novelcompounds of this invention are synthesized by the folinert organicsolvent, in the presence of a free radical initiator. When the reactionis complete, the excess bromine is removed and the3-bromo-2,3-dihydro-2-oxo-l H-l ,4-benzodiazepine-3 -carboxylic acidester hydrobromide intermediate (II) is hydroxylated by addition of analkali metal hydroxide. Preferably the bromination reaction is conductedin methylene chloride in the presence of dibenzoyl peroxide, the excessbromine is removed by evaporation under vacuum and the hydroxylation isaccomplished by the addition of sodium hydroxide. When the hydroxylationis complete, the resulting 2,3-dihydro-3-hydroxy-2-oxol H- 1,4-benzodiazepine-3-carboxylic acid ester (lll) may be obtained byconventional recovery procedures.

Alternatively, when it is desired to synthesize a 3-alkoxy-2,3-dihydro-2-oxol H- l ,4-benzodiazepine-3-carboxylic acid esterhydrobromide (IV) and a3-alkoxy-2,3-dihydro-2-oxolH-l,4-benzodiazepine-3-carboxylic acid ester(V) of the present invention, the bromination and alkanolation steps maybe carried out simultaneously or separately as hereinbefore described inthe preparation of the 2,3-dihydro-3-hydroxy-2-oxo-lH-l,4-benzodiazepine-3-carboxylic acid esters (lll). When thesesteps are carried out simultaneously, an appropriate 2,3-dihydro-2-oxo-lH- l ,4-benzodiazepine-3-carboxylic acid ester (1) is admixed with aslight molar excess of bromine and an alkanol, in a reaction inertorganic solvent containing a free radical initiator. The particularalkanol employed will determine the particular alkoxy substituent (R forexample, if ethanol is employed the (R substituent will be an ethoxygroup. When the reaction is complete, the resulting3-alkoxy-2,3-dihydro-2-oxol H- l ,4-benzodiazepine-3-carboxylic acidester, hydrobromide (IV) is separated and purifled by concentration andcrystallization.

The 3-alkoxy-2,3-dihydro-2-oxo-1l-l-l ,4-benzodiazepine-- lowingschematic sequence of reactions. 3-carboxylic acid ester hydrobromides(IV) of the present in- H 0 c Q 0 R5 H /CH C O 0 R5 Condensation C 0 0 Rm (ll-0 NHKCI R2 5 R3 Rn I) l Bromination 0 0 0 H H H R1 N-- R1 N Rt NRs Ra B r N eutrali- I Zation Alkanolatton COORa COOR5 COOR5 R2 *N R2 fR2 =1? R3 v M um (W HBr (II) Decarboxylation l Hydroxylation H 0 11 R1N- Rt N 1 OH H U c 0OR5 R2 13 \|:=N

The condensation reaction between a slight molar excess of adialkylaminomalonate and an appropriate 2-aminobenzoyl compound iseffected by heating a mixture of these reactants in pyridine at atemperature from about 80 C. to about 150 C. for a period of from about4 to about 16 hours. Preferably this reaction is conducted at the refluxtemperature of the reaction mixture for about 5 hours. After thereaction is complete, the reaction mixture is cooled and the2,3-dihydro- 2-oxo-lH-l,4-benzodiazepine-3-carboxylic acid ester (1) isobtained by conventional methods such as extraction, concentration andcrystallization.

When it is desired to prepare a 2,3-dihydro-3-hydroxy-2- oxo-lH-l,4-benzodiazepine-S-carboxylic acid ester (III) of this invention, anabove prepared 2,3-dihydro-2-oxo-l H-l,4- benzodiazepine-3-carboxylicacid ester (l) is brominated by contact with a slight molar excess ofbromine, in a reaction (III) vention may be converted to thecorresponding free ester (V) by reacting the ester hydrobromide (IV)with a base. Preferably, this reaction is conducted in a reaction inertorganic solvent, such as chloroform by contact with a saturated sodiumbicarbonate aqueous solution. When neutralization is complete, the3-alkoxy-2,3-dihydro-2-oxo-l H- l ,4- benzodiazepine-3-carboxylic acidester (V) is obtained by standard recovery procedures well known tothose skilled in the chemical art, e.g., extraction, evaporation andcrystallizatron.

Decarboxylation of a 3 alkoxy-2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-S-carboxylic acid ester, (V) or its correspondinghydrobromide (W) is accomplished by dissolving the ester (V) orhydrobromide (IV) in water or an alkanol in the presence of an alkalimetal hydroxide at a temperature ranging from about 40 C. to about 60 C.for a period of from 4 to 24 hours. Preferably, this decarboxylation isconducted at a temperature about 55 C. for approximately 16 hours. Whenthe ester hydrolysis is complete, the compound is decarboxylated by theaddition of a mineral acid and the crystalline 3-alkoxy-l,3-dihydro-2H-l ,4-benzodiazepin-2-one (V1) is obtained by filtrationand recrystallization of the resulting precipitate.

in accord with another process aspect of the present invention, a3-alkoxy-l,3-dihydro-2H-l,4-benzodiazepin-2-one (VI) is converted to itscorresponding l ,3-dihydro-3-hydroxy- 2H-l,4-benzodiazepin-2-ones (Vll).This process is exemplified in the following reaction scheme:

wherein R,, R R and R are as defined above, except that R is not loweralkoxyphenyl in formula (Vll).

Dealkylation of a 3-alkoxy-1,3-dihydro-2H-l,4- benzoidiazepin-Z-one (VI)is accomplished by admixture with boron tribromide, in an inertatmosphere, at a temperature from about C. to about 40 C. for a periodof about minutes to about 5 hours. Preferably this reaction is conductedin a nitrogen atmosphere at a temperature about 25 C. for 1 hour. Afterthe reaction is complete, the reaction mixture is cooled, filtered andthe filtrate neutralized by the addition of a base. Thereafter, acrystalline l,3-dihydro-3-hydroxy-2H-l,4-benzodiazepin-2-one (Vll) isseparated by standard methods, such as, filtration andrecrystallization.

By reaction-inert organic solvent as employed herein is meant an organicsolvent which dissolves the reactants but will not prevent or interferewith their interaction. For example, some such solvents are methylenechloride, benzene, 1,2- dimethoxyethane, tetrahydrofuran, dioxane,carbon tetrachloride and chloroform. A free radical initiator is definedas a catalyst for a free radical chemical reaction, examples of suchcatalysts are sunlight, dibenzoyl peroxide, benzoyl peroxide and acetylperoxide. Mineral acids, as employed herein, are exemplified by thefollowing: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitricacid, sulfuric acid and phosphoric acid. The time and temperature rangesemployed above are not critical and simply represent the most convenientranges consistent with carrying out the reaction in a minimum of timewithout undue difficulty. Thus, reaction temperatures appreciably belowthese can be used, but their use considerably extends the reaction time.Similarly, reaction temperatures higher than those mentioned can beemployed with a concomitant decrease in reaction time. The amount ofsolvent used in the aforesaid reactions is not critical, it being onlynecessary to use a sufficient amount of solvent to provide a reactionmedium for the particular reactants.

Many of the reactants employed in the processes of this invention areknown compounds which are readily available from commercial sources,while the remainder can easily be prepared in accordance with standardorganic procedures well known to those skilled in the art.

In accord with the present invention, the new and novel 2,3- dihydro-2-oxo-l H-l ,4-benzodiazepine-3-carboxylic acid esters;2,3-dihydro-3-hydroxy-2-oxo-l H-l ,4-benzodiazepine- 3-carboxylic acidesters and 3-alkoxy-2,3-dihydro-2-oxo-lH-l,4-benzodiazepine-3-carboxylic acid esters of the present inventionhave been found to possess interesting pharmaceutical properties whichrender them useful as synthetic medicinals. More particularly, thesecompounds, in standard pharmacological tests, have exhibited utility ascentral nervous system depressants. In addition to their pharmacologicalutility, these new and novel compounds may be utilized as intermediatesin the production of 3-alkoxy-l,3-dihydro-2H-l,4- benzodiazepin-Z-ones,and l,3-dihydro-3-hydroxy-2H-l,4- benzodiazepin-Z-ones.

When the compounds of this invention are employed as central nervoussystem depressants, they may be administered alone or in combinationwith pharmaceutically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration and standard pharmaceutical practice. Forexample, they may be administered orally in the form of tablets orcapsules containing such excipients as starch, milk sugar, certain typesof clay and so forth. They may be administered sublingually in the formof troches or lozenges in which the active ingredient is mixed withsugar and corn syrups, flavoring agents and dyes; and then dehydratedsufficiently to make it suitable for pressing into a solid form. Theymay be administered orally in the form of solutions which may containcoloring and flavoring agents or they may be injected parenterally, thatis intramuscularly, intravenously or subcutaneously. For parenteraladministration they may be used in the form of a sterile solutioncontaining other solutes, for example, enough saline or glucose to makethe solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, treatmentis initiated with small dosages substantially less than the optimum doseof the compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects and preferably at alevel that is in the range of from about 1 mg. to about 500 mg. per kg.of body weight per day, although as aforementioned variations willoccur. However, a dosage level that is in the range of from about 5 mg.to about 50 mg. per kg. of body weight per day is most desirablyemployed in order to achieve effective results.

The following examples are given by way of illustration and are not tobe construed as limitations of this invention, many variations of whichare possible without departing from the scope and spirit thereof.

EXAMPLEl 2-Amino-S-chlorobenzophenone (44.0 g., 0.190 mole) and 20.0 g.(0.095 mole) of diethylaminomalonate hydrochloride dissolved in ml. ofpyridine are heated at reflux in an oil bath (temperature C.) for 1hour. An additional 30.0 g. (.142 mole) of diethylaminomalonatehydrochloride is added in three, 20-ml. portions of pyridine at halfhour intervals. A constant volume of solvent is maintained bydistillation of pyridine from the reaction mixture during the additionperiod. After a total reaction time of 4.75 hours, the pyridine isremoved in vacuo and the viscous residue is taken up in benzene andextracted with three portions of water. The benzene extract is driedover anhydrous magnesium sulfate and concentrated in vacuo to a viscousoil. Treatment of the oil with 140 ml. of acetonitrile yields 8.65 g.(13.2%) of 7- chloro-2,3-dihydro-2-oxo-5-phenyl-I H-l,4-benzodiazepine-3- carboxylic acid, ethyl ester, m.p. 227228 C.

Calcd. for C,,,H, N O Cl: C, 63.08; H, 4.41; Cl, 10.35; N, 8.l7. Found:C, 63.09; H, 4,23; CI, 10.7; N, 8.52.

In a similar manner, 2-aminobenzophenone is reacted withdimethylaminomalonate hydrochloride to obtain 2,3-dihydro-2-oxo-5-phenyll H- l ,4-benzodiazepine-3-carboxylic acid, methyl ester.

EXAMPLE u 2-Amino-5-nitrobenzophenone (45.0 g.) and (20.0 g.) ofdiethylaminomalonate hydrochloride dissolved in 150 ml. of pyridine areheated at reflux in an oil bath for 1 hour. Additional 30.0 g. ofdiethylaminomalonate hydrochloride is added in three portions at20-minute intervals in 25-ml. portions of pyridine. A constant volume ofsolvent is maintained by distillation of pyridine from the reactionmixture during the addition period. After a total reaction time of 12hours, the pyridine is removed in vacuo and the viscous residue is takenup in benzene and extracted with three portions of water. The benzeneextract is dried over anhydrous magnesium sulfate and concentrated invacuo to a viscous oil. Treatment of the oil with ethanol yields2,3-dihydro-7-nitro-2-oxo-5-phenyl- 1H- 1 ,4-benzodiazepine-3-carboxylicacid, ethyl ester.

In a similar manner, 2-amino-6-ethyl sulfonylbenzophenone is reactedwith diethylaminomalonate hydrochloride to synthesize6-ethylsulfonyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4

'-benzodiazepine-3-carboxylic acid, ethyl ester.

EXAMPLE III 2-Amino-5-bromobenzophenone (40.0 g.) and (20.0 g.) ofdipropylaminomalonate hydrochloride dissolved in 150 ml. of pyridine areheated at reflux for 1 hour. An additional 30.0 g. ofdipropylaminonomalonate hydrochloride is added in three portions at halfhour intervals in 20-ml. portions of pyridine. A constant volume ofsolvent is maintained by distillation of pyridine from the reactionmixture during the addition period. After a total reaction time of 16hours, the pyridine is removed in vacuo and the viscous residue is takenup in benzene and extracted with water. The benzene extract is driedover anhydrous magnesium sulfate and concentrated in vacuo.Recrystallization from methanol yields 7-bromo-2,3-dihydro-2-oxo-5-phenyl-1H-l,4-benzodiazepine-3-carboxylic acid, propylester.

Similarly, 7,9-dichloro-2,3-dihydro-2-oxo-5-phenyl' l H-1 ,4-benzodiazepine-3-carboxylic acid, ethyl ester is synthesized.

EXAMPLE IV When the procedure of Examples 1 to 111 is employed, reactingan appropriate 2-aminobenzoyl compound with adi(lower)alkylaminomalonate, the following 2,3-dihydro-2- oxo-l H-l,4-benzodiazepine-3-carboxylic acid esters are obtained:

7-trifluoromethyl-2,3-dihydro-2-oxo-5-(2-thienyl)-1H-l,4-benzodiazepine-S-carboxylic acid, methyl ester;

8-dichloromethyl-5-(p-chlorophenyl)-2,3-dihydro-2-oxo-1H-l,4-benzodiazepine-3-carboxylic acid, propyl ester;

2,3-dihydro-7-methylsulfonyl-2-oxo-5-(p-tolyl)-lH-1,4-benzodiazepine-3-carboxylic acid, ethyl ester;

5-( m-chlorophenyl)-2,3-dihydr-2-oxol H-1 ,4-benzodiazepine-3-carboxylic acid, methyl ester;

2,3-dihydro-8-iodo-5-(p-methoxyphenyl)-2-oxol H- l ,4-benzodiazepine-3-carboxylic acid, ethyl ester;

-(p-trifluoromethylphenyl)-2,3-dihydro-2-oxo- 1 H-1 ,4-benzodiazepine-3-carboxylic acid,methyl ester;

8-chloro-5-(m-ethylphenyl)-2,3-dihydro-2-oxo-1H-l ,4-benzodiazepine-3-carboxylic acid, butyl ester;

5-(p-chlorophenyl)-2,3-dihydro-2-oxo-l H-1,4-benzodiazepine-S-carboxylic acid, ethyl ester;

7-chloro-2,3-dihydro-2-oxo-5-(p-propoxyphenyl)-1H-1,4-benzodiazepine-3-carboxylic acid, methyl ester; and

7-chloro-5-(o-chlorophenyl)-2,3-dihydro-2-oxo-l H-1 ,4-benzodiazepine-3-carboxylic acid, ethyl ester.

EXAMPLE V 7-Chloro-2,3-dihydro-2-oxo-5-phenyl-lH-1,4-benzodiazepine-3-carboxylic acid, ethyl ester (1.50 g., 4.38 m

mole) dissolved in 75 ml. of methylene chloride and 0.5 ml. of

methanol is treated with a solution of 0.842 g. (5.27 m mole) ofbromine. The mixture is then treated with 30 mg. of

dibenzoyl peroxide and stirred at 27 C. for 61 hours. Thereafter thesolvent and excess reagent are evaporated on the rotary evaporator togive an orange oil. Treatment of the oil with ethyl acetate affords1.185 g. of 7-chloro-2,3-dihydro- 3-methoxy-2-oxo-5-phenyl-1H-l,4-benzodiazepine-3-carboxylic acid, ethyl ester, hydrobromide as yellowcrystals, m.p. ll81C.

7-Chloro-2,3-dihydro-3-methoxy-5-phenyl-2-oxo-1H-l ,4-benzodiazepine-S-carboxylic acid, ethyl ester, hydrobromide (0.8 g.)partially dissolved in 15 ml. of chloroform is agitated with 10 ml. ofsaturated sodium bicarbonate solution. The chloroform extract is washedwith water and dried over anhydrous magnesium sulfate. Evaporation ofthe chloroform leaves an oily residue which crystallizes inethanol-water. Recrystallization from ethanol-water yields 0.45 g. of 7chloro-2,3-dihydro-3-methoxy-2-oxo-S-phenyl-l H-1 ,4-benzodiazepine-3-carboxylic acid, ethyl ester, m.p. 168"-l70 C.

Calcd. for C H CIN O; C, 61.22; H, 4.60; Cl, 9.51; N, 7.52. Found:C,60.96;H,4.63;Cl, 9.7;N,7.33.

Similarly, 2,3-dihydro-2-oxo-5-phenyl-l H- l ,4-benzodiazepine-3-carboxylic acid, methyl ester is dissolved in benzeneand ethanol and then treated with bromine and dibenzoyl peroxide toproduce 3-ethoxy-2,3-dihydro-2-oxo-5- phenyl- 1 H- 1,4-benzodiazepine-3-carboxylic acid, methyl ester, hydrobromide. Whenthe hydrobromide is neutralized as described above, there is obtained3-ethoxy-2,3-dihydro-2- oxo-5-phenyl- 1 H- l,4-benzodiazepine-3-carboxylic acid, methyl ester.

EXAMPLE VI 2,3-dihydro-7-nitro-2-oxo-5-phenyl- 1 PM ,4-benzodiazepine-3-carboxylic acid, ethyl ester (1.50 g.) dissolved in 75ml. of benzene and 0.94 ml. of propanol is treated with a solution of0.84 g. of bromine. The mixture is treated with 30 mg. of benzoylperoxide and stirred at 25 C. for 50 hours. The solvent and excessreagent are then evaporated on the rotary evaporator. Treatment of theresidue with ether affords 2,3-dihydro-7-nitro-2-oxo-5-phenyl-3-propoxylH- l ,4- benzodiazepine-3-carboxylic acid, ethyl ester, hydrobromide.

The above prepared 2,3-dihydro-7-nitro-2oxo-5-phenyl-3-propoxy-lH-l,4-benzodiazepine-3-carboxylic acid, ethyl ester,hydrobromide partially dissolved in chloroform is agitated with 25 ml.of saturated sodium bicarbonate solution. The chloroform extract iswashed with water and dried over anhydrous magnesium sulfate.Evaporation of the chloroform leaves a residue which crystallizes inethanol-water. Recrystallization from ethanol-water yields2,3-dihydro-7-nitro-2-oxo- 5 -phenyl-3-propoxy- 1 H- 1,4-benzodiazepine-3-carboxylic acid, ethyl ester.

EXAMPLE VII 7-Bromo-2,3-dihydro-2-oxo-5-phenyl-1H-l ,4-benzodiazepine-3-carboxylic acid, ethyl ester (3.0 g.) dissolved in ml.of 1,2-dimethoxyethane and 1.3 ml. of ethanol is treated with a solutionof 1.49 g. of bromine. The mixture is treated with 60 mg. of acetylperoxide and stirred at 30 C. for 45 hours. The solvent and excessreagent are evaporated on the rotary evaporator. Treatment of theresidue with ethyl acetate affords 7-bromo-3-ethoxy-2,3-dihydro-2-oxo-S-phenyl- 1 H- 1 ,4-benzodiazepine-3-carboxylic acid, ethyl ester,hydrobromide.

7-Bromo-3-ethoxy-2,3-dihydro-2-oxo-5-phenyl-1H-l,4-benzodiazepine-3-carboxylic acid, ethyl ester, hydrobromide partiallydissolved in 50 ml. of chloroform is agitated with 10 ml. of 1N sodiumhydroxide solution. The chloroform extract is washed with water, driedover anhydrous magnesium sulfate and evaporated. The residue iscrystallized in methanol-water to yield7-bromo-3-ethoxy-2,3-dihydro-2-oxo-5-phenyl-1H-l,4-benzodiazepine-3-carboxylic acid, ethyl ester.

EXAMPLE VIII Employing the procedures described in Examples V to V1],the following 2,3-dihydro-2-oxo-lH-1,4-benzodiazepine-3- carboxylic acidesters are prepared:

7-trifluoromethyl-2,3-dihydro-3-methoxy-2-oxo-5-(2-thienyl)-l H- l,4-benzodiazepine-3-carboxylic acid, methyl ester;

8-dichloromethyl-5-(p-chlorophenyl)-2,3-dihydro-2-oxo-3-propoxy-lH-l,4-benzodiazepine-3-carboxylic acid, propyl ester; and

3-butoxy-2,3-dihydro-7-methylsulfonyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid, ethyl ester.

EXAMPLE lX 7-Chloro-2,3-dihydro-2-oxo-5-phenyl-1H-l,4-benzodiazepine-3-carboxylic acid, ethyl ester 1.50 g., 4.38 m mole)dissolved in 75 ml. of methylene chloride and 0.5 ml. of methanol istreated with a solution of0.842 g. (5.27 m mole) of bromine. The mixtureis treated with 30 mg. of dibenzoyl peroxide and stirred at 27 C. for 61hours. The solvent and excess reagent are evaporated on the rotaryevaporator to an orange oil residue. Treatment of the oil with ethylacetate affords 1.185 g. of 7-chloro-2,3-dihydro-3-methoxy-2-oxo-5-phenyl-lH-l,4benzodiazepine-3-carboxylic acid, ethyl ester, hydrobromideas yellow crystals, m.p. l80-18l C. The crystalline material is carriedto the next step without additional purification.

The unpurified above prepared 7-chloro-2,3-dihydro-3-methoxy-2-oxo'5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid, ethylester, hydrobromide (455 mg., 1.0 m mole) is slurried in 6 ml. of waterand 1 m1. of 4N sodium hydroxide and the mixture is stirred and heatedat 50 C. lnitially all the solid dissolves but after 5 minutes 300 mg.ofa white crystalline sodium salt separates. A 261 mg. portion of thesodium salt is heated at 58 C. in a solution of 0.8 ml. of 4N sodiumhydroxide for 16 hours. Acidification of the chilled solution with 1Nhydrochloric acid yields 30 mg. of crude product, m.p. 183-187 C.Recrystallization from acetonitrile yields 7- chloro- 1,3-dihydro-3-methoxy5-phenyl-2H-l ,4- benzodiazepin-2-one, m.p. 230-233C.

EXAMPLE X The unpurified 2,3-dihydro-7-nitro-2-oxo-5-phenyl-3-propoxy-lH-l,4-benzodiazepine-3-carboxylic acid, ethyl ester,hydrobromide (492 mg.), as prepared in Example V1, is slurried in 6 ml.of ethanol and 2 ml. of 2N potassium hydroxide and the mixture stirredand heated at 25 C. for 20 minutes. Thereafter, the precipitatedmaterial is again heated at 40 C. in 6.0 ml. of 1N potassium hydroxidefor 24 hours. Upon cooling, the solution is acidified with 0.5 Nsulfuric acid. The resulting precipitate is recrystallized from ethanolto obtain 1,3-dihydro-7-nitro-5-phenyl-3-propoxy-2H-1,4-benzodiazepin-Z-one.

Similarly, 7-trifluoromethyl-1,3-dihydro-3-methoxy-5-(2- thienyl)-2H- l,4-benzodiazepin-2-one is obtained.

EXAMPLE XI The unpurified 7-bromo-3-ethoxy-2,3-dihydro-2-oxo-5-phenyl-lH-l,4-benzodiazepine-3-carboxylic acid, ethyl ester,hydrobromide (1.28 g., 2.5 m mole), as prepared in Example V11, isslurried in 12 ml. of methanol and 2 ml. of 5N sodium hydroxide and themixture is stirred and heated at 75 C. for 5 minutes. Thereafter, theprecipitated material is separated and admixed with 2.75 ml. of 5Nsodium hydroxide and heated at 50 C. for 5 hours. Upon cooling, thereaction mixture is acidified with 1N hydrochloric acid and theresulting precipitate recrystallized from methanol to yield 7-bromo3-ethoxy- 1 ,3-dihydro-5-pheny-2l-l-1,4-benzodiazepin-2-one.

Employing the above described procedure, the following compounds areobtained:

5-(p-trifluoromethylphenyl)-1,3-dihydro-3-methoxy-2H-1,4-benzodiazepin-2-one;

3-butoxy-8-chloro-5-(m-ethylphenyl)-1,3-dihydro-2H-l ,4-benzodiazepin-Z-one;

5-(p-dichloromethylphenyl)-l,3-dihydro-3-meth0xy-2H-1,4-benzodiazepin-2-one;

3-ethoxy-l,3-dihydro-7-methylsulfonyl-5- phenyl -2H-1,4-benzodiazepin-Z-one; and

3-ethoxy-1,3-dihydro-5-phenyl-2H-l ,4-benzodiazepin-2- one.

EXAMPLE Xll 7-Chloro-2,3-dihydro-2-oxo-5-phenyll H-1 ,4-benzodiazepine-3-carboxylic acid, ethyl ester 1.50 g., 4.38 m mole)dissolved in 75 ml. of methylene chloride and 0.5 ml. of methanol istreated with a solution of 0.842 g. (5.27 m mole) of bromine. Themixture is treated with 30 mg. of dibenzoyl peroxide and stirred at 27C. for 61 hours. The solvent and excess reagent are evaporated on therotary evaporator to give an orange oil. Treatment of the oil with ethylacetate affords 1.185 g.of7-chloro-2,3-dihydro-3-methoxy-2-oxo-5-phenyl-1 H-l,4-benzodiazepine-3-carboxylic acid, ethyl ester, hydrobromide as yellowcrystals, m.p. -18l C. The crystalline material is carried to the nextstep without additional purification.

The unpurified above prepared 7-chloro-2,3-dihydro-3-methoxy-Z-oxo-S-phenyl-lH-1,4-benzoidiazepine-3-carboxylic acid, ethylester, hydrobromide (455 mg., m mole) is slurried in 6 ml. of water and1 ml. of 4N sodium hydroxide and the mixture is stirred and heated at 50C. lnitially all the solid dissolves but after five minutes 300 mg. of awhite crystalline sodium salt separates. A 261 mg. portion of the sodiumsalt is heated at 58 C. in a solution of 0.8 ml. of 4N sodium hydroxidefor 16 hours. Acidification of the chilled solution with 1N hydrochloricacid yields 30 mg. of crude product, m.p. l83l87 C. Recrystallizationfrom acetonitrile yields 7-chloro-l,3-dihydro-3-methoxy-5-phenyl-2H-1,4- benzodiazepin-Z-one, m.p.230-233 C.

7-Chloro-1,3-dihydro-3-methoxy-5-phenyl-2H-1,4- benzodiazepin-Z-one (500mg., 1.67 m mole) is added as a finely divided powder to 10 ml. of borontribromide at 27 C. The slurry is then stirred in a nitrogen atmosphereat 27C. for 45 minutes and at 35 C. for 15 minutes. The slurry is pouredslowly into 200 g. ofice-water with stirring and the mixture is allowedto warm to room temperature. The boric acid which separates is filtered,the filtrate neutralized with 4N sodium hydroxide (pH 7-8) and theresulting white solid (mp. l94l98 C.) which separates (approx. 500 mg.)is filtered and washed with water. Recrystallization of this materialyields 15] mg. of 7-chlor0-l,3-dihydro-3-hydroxy-5-phenyl 2H-l,4-benzoidiazepin-2-one, m.p. l99-200 C.

EXAMPLE Xlll EXAMPLE XlV 7-Bromo-3-ethoxy-1,3-dihydro-5-phenyl-2H-1,4-

benzodiazepin-Z-one (0.25 g.), in a finely divided form, is added toboron tribromide (5 ml.) at 10 C. under a helium at mosphere and themixture is stirred for 1 hour at 40 C. Thereafter, the reaction mixtureis slowly poured into 75 g. of ice and the mixture allowed to stand for12 hours. Subsequently, the boric acid is removed by filtration, and thefiltrate neutralized by the addition of 3N sodium hydroxide. Theresulting precipitate is 7-bromo-1,3-dihydro-3-hydroxy-5- phenyl-ZH-l,4-benzodiazepin-2-one.

EXAMPLE XV Employing the general procedure described in Examples X11]and XlV, the following 3-hydroxy-1,3-dihydro-2H-l,4-benzodiazepin-Z-ones are produced:

8-chloro-5-phenyll ,3-dihydro-3-hydroxy-2H- l ,4- benzodiazepin-Z-one;

7 trifluoromethyl-l ,3-dihydro-3-hydroxy-5-( 2-thienyl)-2H- 1,4-benzodiazepin-2 one;

5-( p-chlorophenyl l ,3-dihydro-3-hydroxy-2H-l ,4- benzodiazepin-Z-one;

1,3-dihydro-3-hydroxy5-phenyl-2H- l ,4-benzodiazepin-2- one; and

7-chloro-5-(o-chlorophenyl )4 ,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one.

EXAMPLE XVl A solution of 4.00 g. (11.7 m mole) of 7chloro-2,3-dihydro-Z-oxo-S-phenyll H-l ,4-benzodiazepine-3-carboxylic acid, ethylester in 225 ml. of chloroform containing 0.75 percent of ethanol isslowly admixed with a solution of 2.30 g. 14.4 m mole) of bromine in 25ml. chloroform and the resulting orange solution is stirred at 26 C. for20 hours. Thereafter, the solvent and excess bromine are removed on therotary evaporator leaving an orange residue. Treatment of the residuewith ethyl acetate yields 2.65 g. of yellow solid hydrobromide. A 1.1 g.portion of the solid is twice recrystallized from ethanol water to give0.467 g. of 7-chloro-2,3- dihydro-3-ethoxy-2-oxo-5-phenyll H- l,4-benzodiazepine-3- carboxylic acid, ethyl ester, hemiethanolate, m.p.l64-l66 C. Calcd. for C, l-l,,,ClN O,.1/2 C,H,,OH: C, 61.53; H, 5.41;Cl, 8.65; N, 6.84 Found: C, 61.46; H, 5.44; Cl, 8.7; N, 6.81.

EXAMPLE XVll 7-Chloro-2,3-dihydro-2-oxo 5-phenyll H- l ,4-benzodiazepine-3-carboxylic acid, ethyl ester (5.00 g., 14.5 m mole)dissolved in 200 ml. of methylene chloride is gradually admixed with2.79 g. (17.5 m mole) of bromine in 50 ml. of methylene chloride. Thesolution is treated with 75 mg. of dibenzoyl peroxide and stirred at 27C. for 16 hours. The solvent and excess bromine are evaporated in vacuoand the residue dissolved in 50 ml. of 1,2-dimethoxyethane and ml. ofwater. The mixture is adjusted to pH 8 (Hydrion paper) with 4N sodiumhydroxide solution and stirred for 35 minutes at 27 C. The volatilesolvents are removed in vacuo and the mixture treated with 17 ml. of 4Nsodium hydroxide, thereby causing a yellow solid to separate (5.4 g.).

A 4.0 g. portion of this solid is partially dissolved in ml. of aqueousethanol, filtered, and the filtrate acidified dropwise with 6Nhydrochloric acid. Filtration of the needles which separate yields 1.1g. of crude product, m.p. l74-l78 C. When recrystallized fromacetonitrile, there is obtained 7-chloro-2,3-dihydro-3-hydroxy-2-oxo-5-phenyl-1H-1 ,4-benzodiazepine-3-carboxylic acid, ethyl ester, m.p. l80l8 1 .5 C.

Calcd. for C, H,,,CIN O C, 60.24; H, 4.21; Cl, 9.88; N, 7.81 Found: C,60.51; H, 4.30; Cl, 9.86; N, 8.14.

In a similar manner, 8-dichloromethyl-5-(p-chlorophenyl)-2,3-dihydro-3-hydroxy-2-oxol H- l ,4-benzodiazepine-3-carboxylic acid,methyl ester; 7-trifluoromethyl-2,3-dihydro-3-hydroxy-2-oxo-5-(2-thienyl)-1GH-l ,4benzodiazepine-3-carboxylic acid,propyl ester; and 2,3-dihydro-3-hydroxy-7-- nitro-2-oxo-5-phenyll H- l,4-benzodiazepine-3-carboxylic acid, ethyl ester are produced.

EXAMPLE XVllI 7Bromo-2,3-dihydro-2-oxo-5-phenyll H-1 ,4-benzodiazepine-S-carboxylic acid, ethyl ester (15.0 g.) dis solved in200 ml. of dioxane is treated gradually with 9.0 g. of bromine in 150ml. of dioxane. The solution is admixed with 250 mg. of benzoyl peroxideand stirred at 20 C. for 24 hours. The solvent and excess bromine areevaporated in vacuo and the residue dissolved in 150 ml. of1,2-dirnethoxyethane and 60 ml. of water. The mixture is adjusted to pH8 (Hydrion paper) with 1N potassium hydroxide solution and stirred for20 minutes at 20 C. The volatile solvents are removed in vacuo and themixture treated with about ml. of 2N potassium hydroxide. The resultingprecipitate is dissolved in ml. of aqueous methanol, filtered, and thefiltrate acidified by the addition of 2N hydrochloric acid. Theresulting precipitate is filtered and recrystallized from ethanol toobtain 7-bromo- 2,3-dihydro-3-hydroxy-2-oxo-5-phenyl-1H-l ,4-benzodiazepine-3-carboxylic acid, ethyl ester.

Employing the above procedure, the following compounds are obtained:

8-chloro-5-(p-chloropenyl)-2,3-dihydro'3-hydroxy-2-oxolH-l,4-benzodiazepine-3-carboxylic acid, methyl ester; and

2,3-dihydro-3-hydroxy-2-oxo-5-phenyll H-1 ,4-benzodiazepine-3-carboxylic acid, propyl ester.

EXAMPLE XlX 7,8-Dichloro-2,3-dihydro-2-oxo-5-phenyl- 1 11-1 ,4-benzodiazepine-3-carboxylic acid, methyl ester (5.00 g.) dissolved in200 ml. of tetrahydrofuran is gradually admixed with 3.0 g. of brominein 50 ml. of tetrahydrofuran. The solution is treated with 85 mg. ofacetyl peroxide and stirred at 10 C. for 40 hours. The solvent andexcess bromine are evaporated in vacuo and the residue dissolved in 50ml. of 1,2-dimethoxyethane and 20 ml. of water. The mixture is adjustedto pH 8 with 1N potassium hydroxide solution and stirred for 1 hour at25 C. The volatile solvents are removed in vacuo and the mixture treatedwith 1N potassium hydroxide, causing a solid to separate. The solid isseparated, dissolved in aqueous ethanol and acidified. The resultingprecipitate is separated and recrystallized from methanol to yield7,8-dichloro-2,3- dihydro-3-hydroxy-2-oxo-5-phenyll H-l,4-benzodiazepine-3- carboxylic acid, methyl ester.

What is claimed is:

1. A compound selected from the group consisting of those having theformula:

wherein R and R are each selected from the group consisting of hydrogen,halogen, nitro, halo(lower)alkyl, and lower a1- kylsulfonyl; R isselected from the group consisting of thienyl, phenyl, halophenyl, loweralkoxyphenyl, and halo(lower)alkylphenyl; R is selected from the groupconsisting of, hydroxy and lower alkoxy; and R is (lower) alkyl.

2. 7-chloro-2,3-dihydro-3-hydroxy-2-oxo-5-phenyll H- l ,4-benzodiazepine-3-carboxylic acid, ethyl ester.

3. A compound as described in claim 1 which is: 7-chloro-2,3-dihydro-3-hydroxy-2-oxo-5-phenyll H- l ,4-benzodiazepine-3-earboxylic acid, ethyl ester.

4. A compound as described in claim 1 which is: 7-chloro- 2,3-dihydro-3-ethoxy-2-oxo-5-phenyl- 1 H- 1 ,4-benzodiazepine-3-carboxylic acid, ethyl ester, hemi ethanolate.

5. A compound as described in claim 1 which is: 7-chloro-2,3-dihydro-3-methoxy-2-oxo-5-phenyll H- l ,4-benzodiazepine-3-carboxylic acid, ethyl ester.

6. A process which comprises:

a. condensing a di(lower)alkylaminomalonate with a 2- aminobenzoylcompound of the formula:

COOR5 halo(lower)alkylphenyl, in pyridine, to form a 2,3-dihydro-2-oxo-ll-l-l ,4-benzodiazepine-3-carboxylic acid ester;

b. brominating and alkanolating said carboxylic acid ester to form a3-alkoxy-2,3-dihydro-Z-oxol H-l ,4- benzodiazepine-3-carboxylic acidester, hydrobromide;

c. neutralizing, hydrolyzing and decarboxylating said3-alkoxy-3-carboxylic acid ester, hydrobromide to produce a 3-alkoxy-l,3-dihydro-2H- l ,4-benzodiazepine-2-one of the formula:

i W V R R K 4 R:

wherein R,, R and R are defined as above and R is alkyl.

7. A process as described in claim 6 wherein:

a. the bromination and alkanolation are conducted, in a reaction inertorganic solvent, in the presence of a free radical initiator;

b. the neutralization and the hydrolysis are conducted by the additionof an alkali metal hydroxide; and

c. the decarboxylation is conducted by the addition of a mineral acid.

8. A process as described in claim 6 wherein:

a. the bromination and alkanolation are conducted, in methylenechloride, in the presence of dibenzoyl peroxide;

b. the neutralization and the hydrolysis are conducted by the additionof sodium hydroxide; and

c. the decarboxylation is conducted by the addition of hydrochloricacid.

9. A process for the production of a compound of the formula:

R. -N OH wherein R and R are each selected from the group consisting ofhydrogen, halogen, nitro, halo(lower)alkyl and lower alkylsulfonyl and Ris selected from the group consisting of thienyl, halophenyl, andhalo(lower)alkylphenyl, which comprises contacting a compound selectedfrom the group consisting of those having the formula:

wherein R R and R are defined as above and R, is lower alkyl with borontribromide, in an inert atmosphere, at a temperature range from about 0C. to about 40 C. for a period of from about 15 minutes to about hours.

10. A process as described in claim 9 wherein: a. the inert atmosphereis nitrogen; b. the temperature is about 25 C.; and c. the reactionperiod is about 1 hour. 11. A process which comprises: a. condensing adialkylaminomalonate with a 2- aminobenzoyl compound of the formula:

wherein R and R are each selected from the group consisting of hydrogen,halogen, nitro, halo(lower)alkyl and lower alkylsulfonyl and R isselected from the group consisting of thienyl, phenyl, halophenyl, andhalo(lower)alkylphenyl, in pyridine, to form a 2,3-dihydro-2-oxo-l H-l,4- benzodiazepine-3-carboxylic acid ester;

b. brominating and alkanolating said carboxylic acid ester to form3-alkoxy-2,3-dihydro-2-oxo-l H-l ,4- benzodiazepine-3-carboxylic acidester, hydrobromide;

c. neutralizing, hydrolizing and decarboxylating said carboxylic acidester hydrobromide to obtain a 3-alkoxyl ,3- dihydro-ZH-l,4-benzodiazepin-2-one; and

reacting said 3-alkoxy-l,3-dihydro-2H-1,4-benzodiazepin-2-one with borontribromide, in an inert atmosphere, at a temperature range from about 0C. to about 40 C. for a period from about 15 minutes to about 5 hours toproduce a l,3-dihydro-3-hydroxy-2H-l,4- benzodiazepin-Z-one of theformula:

wherein R R and R are defined as above.

12. A process as described in claim 11 which comprises:

a. condensing 2-amino-5-chlorobenzophenone with a dialkylaminomalonate,in pyridine, at reflux temperatures for about five hours to form a7-chloro-2,3-dihydro-2-oxo-5- phenyl-l H- l,4-benzodiazepine-3-carboxylic acid ester;

b. brominating and alkanolating said carboxylic acid ester by reactionwith bromine and an alkanol, in a reaction inert organic solvent in thepresence of a free radical initiator to produce a3-alkoxy-7-chloro-2,3-dihydro-2-oxo- S-phenyll H- l,4-benzodiazepine-3-carboxylic acid, ester, hydrobromide;

c. neutralizing said carboxylic acid ester, hydrobromide by the additionof an alkali metal hydroxide and then hydrolyzing and decarboxylatingthe carboxylic acid ester to obtain a3-alkoxy-7-chloro-l,3-dihydro-5-phenyl-2H- l ,4-benzodiazepin-2-one; and

d. reacting said 3-alkoxy-7-chloro-l,3-dihydro-5-phenyl- 2H- l,4-benzodiazepin-2-one with boron tribromide, in an inert atmosphere, ata temperature range from 0 C. to about 40 C. for a period of from aboutl5 minutes to about 5 hours to produce 7-chloro-l,2-dihydro-3-hydroxy-5-phenyl-2H- l ,4-benzodiazepin'2-one.

13. A process as described in claim 12 which comprises:

a. condensing 2-amino-5-chlorobenzophenone with diethylaminomalonatehydrochloride, in pyridine, at reflux temperatures for five hours toform a 7-chloro-2,3- dihydro-2-oxo-5-phenyll H-l,4-benzodiazepine-3-carboxylic acid, ethyl ester;

b. brominating and methanolating said carboxylic acid, ethyl ester byreaction with bromine and methanol, in methylene chloride, in thepresence of dibenzoyl peroxide to produce7-chloro-2,3-dihydro-3-methoxy-2-oxo-5-phenyl-lH-l,4-benzodiazepine-B-carboxylic acid, ethyl ester,hydrobromide;

c. neutralizing said ethyl ester, hydrobromide by the addition of sodiumhydroxide and then hydrolyzing and decarboxylating the ethyl ester toobtain 7-chloro-l ,B-dihydro-3-methoxy-5-phenyl-2H-1,4-benzodiazepin-2-one; and

d. reacting said 7-chloro-l,3-dihydro-3-methoxy-5-phenyl-2H-l,4-benzodiazepin-2-one with boron tribomide, in a nitrogenatmosphere, at about 25 C., for about one hour, to produce7-chloro-l,3-dihydro-3-hydroxy-5-phenyl- 2H-l ,4-benzodiazepin-2-one.

2. 7-chloro-2,3-dihydro-3-hydroxy-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 -carboxylic acid, ethyl ester.
 3. A compound as described in claim 1 which is: 7-chloro-2,3-dihydro-3-hydroxy-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 -carboxylic acid, ethyl ester.
 4. A compound as described in claim 1 which is: 7-chloro-2,3-dihydro-3-ethoxy-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 -carboxylic acid, ethyl ester, hemi ethanolate.
 5. A compound as described in claim 1 which is: 7-chloro-2,3-dihydro-3-methoxy-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 -carboxylic acid, ethyl ester.
 6. A process which comprises: a. condensing a di(lower)alkylaminomalonate with a 2-aminobenzoyl compound of the formula:
 7. A process as described in claim 6 wherein: a. the bromination and alkanolation are conducted, in a reaction-inert organic solvent, in the presence of a free radical initiator; b. the neutralization and the hydrolysis are conducted by the addition of an alkali metal hydroxide; and c. the decarboxylation is conductEd by the addition of a mineral acid.
 8. A process as described in claim 6 wherein: a. the bromination and alkanolation are conducted, in methylene chloride, in the presence of dibenzoyl peroxide; b. the neutralization and the hydrolysis are conducted by the addition of sodium hydroxide; and c. the decarboxylation is conducted by the addition of hydrochloric acid.
 9. A process for the production of a compound of the formula:
 10. A process as described in claim 9 wherein: a. the inert atmosphere is nitrogen; b. the temperature is about 25* C.; and c. the reaction period is about 1 hour.
 11. A process which comprises: a. condensing a dialkylaminomalonate with a 2-aminobenzoyl compound of the formula:
 12. A process as described in claim 11 which comprises: a. condensing 2-amino-5-chlorobenzophenone with a dialkylaminomalonate, in pyridine, at reflux temperatures for about five hours to form a 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ester; b. brominating and alkanolating said carboxylic acid ester by reaction with bromine and an alkanol, in a reaction inert organic solvent in the presence of a free radical initiator to produce a 3-alkoxy-7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 -carboxylic acid, ester, hydrobromide; c. neutralizing said carboxylic acid ester, hydrobromide by the addition of an alkali metal hydroxide and then hydrolyzing and decarboxylating the carboxylic acid ester to obtain a 3-alkoxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one; and d. reacting said 3-alkoxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one with boron tribromide, in an inert atmosphere, at a temperature range from 0* C. to about 40* C. for a period of from about 15 minutes to about 5 hours tO produce 7-chloro-1,2-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one.
 13. A process as described in claim 12 which comprises: a. condensing 2-amino-5-chlorobenzophenone with diethylaminomalonate hydrochloride, in pyridine, at reflux temperatures for five hours to form a 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid, ethyl ester; b. brominating and methanolating said carboxylic acid, ethyl ester by reaction with bromine and methanol, in methylene chloride, in the presence of dibenzoyl peroxide to produce 7-chloro-2,3-dihydro-3-methoxy-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3 -carboxylic acid, ethyl ester, hydrobromide; c. neutralizing said ethyl ester, hydrobromide by the addition of sodium hydroxide and then hydrolyzing and decarboxylating the ethyl ester to obtain 7-chloro-1,3-dihydro-3-methoxy-5-phenyl-2H-1,4-benzodiazepin-2-one; and d. reacting said 7-chloro-1,3-dihydro-3-methoxy-5-phenyl-2H-1,4-benzodiazepin-2-one with boron tribomide, in a nitrogen atmosphere, at about 25* C., for about one hour, to produce 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one. 